A notable portion of the adult US population (2-4%, possibly more) suffers from sleep-disordered breathing, a condition characterized by frequent interruptions of breathing (apneas) and poor sleep. Apneas, whatever their cause, reduce the body's oxygen level (hypoxia) and increase carbon dioxide (CO2, hypercapnia). These changes in blood gases in turn disrupt sleep, affect memory and have adverse health consequences such as increased blood pressure and heart rate, chronic hypertension and exacerbation of diabetes. The main objective of the research is to understand the mechanisms that sustain breathing automaticity, especially during sleep and how failure of this homeostatic mechanism, in turn, disrupts sleep. That involuntary breathing is driven to a large extent by the level of oxygen and carbon dioxide in the blood has been common knowledge for a long time but the mechanisms are still far from clear. We have recently identified a small group of brain neurons, called retrotrapezoid nucleus (RTN), that encode the blood concentration of carbon dioxide. There are multiple reasons to hypothesize that these neurons play a critical role in sustaining breathing during sleep. One especially convincing argument is that RTN neurons fail to develop in a mouse model of a human genetic disease characterized both by the inability to breathe at night and by an insensitivity to carbon dioxide (congenital central hypoventilation syndrome). We have therefore designed experiments to test the function of RTN neurons in fully conscious rodents so that the results might be as relevant as possible to humans. We will also be exploring how RTN neurons respond to hypoxia in an attempt to explain the respiratory insufficiency caused by altitude, which we believe to be caused by a reduced activity of RTN neurons. Finally, neuroanatomical experiments will be conducted to find out the brain circuitry through which RTN neurons stimulate breathing. This project will be carried out using advanced optogenetic and intersectional genetic method and viral vectors designed to propagate in the anterograde or retrograde direction across synapses. This research is expected to clarify how breathing automaticity is maintained during sleep and how respiratory insufficiency or failure in turn disrupts sleep. Novel therapeutic interventions benefiting sleep disordered breathing could result from this research if RTN neurons prove to be as important as we postulate and a way can be found to activate them pharmacologically.